Azacitidine or Decitabine in Epigenetic Priming in Patients with Newly Diagnosed Acute Myeloid Leukemia

Inclusion Criteria

• Patients must have one of the following diagnoses: * Acute myeloid leukemia fulfilling the criteria of the World Health Organization (WHO) classification, or * > 5% but < 20% marrow myeloblasts and evidence of a clonal de novo AML genetic abnormality [e.g., t(8;21), inv(16), t(9;11)], or * Myeloid sarcoma (also referred to as extramedullary myeloid tumor, granulocytic sarcoma, or chloroma), with or without evidence of a leukemia process in the bone marrow or peripheral blood, with confirmation of myeloid differentiation, or * High grade myelodysplastic syndrome (MDS) with greater than 5% blasts, or * Patients with treatment related myeloid neoplasms including AML and MDS, provided their cumulative anthracycline dose has not exceeded 230 mg/m^2 doxorubicin equivalents
• No prior therapy for this malignancy except for one dose of intrathecal therapy and the use of hydroxyurea or low-dose cytarabine (100-200 mg/m^2 per day for one week or less for hyperleukocytosis), and
• Written informed consent according to institutional guidelines, and
• Female patients of childbearing potential must have a negative pregnancy test within 2 weeks prior to enrollment, and
• Male and female participants of reproductive potential must use an effective contraceptive method during the study and for a minimum of 6 months after study treatment

Exclusion Criteria

• Down syndrome
• Acute promyelocytic leukemia (APL)
• BCR-ABL1 chronic myeloid leukemia in blast crisis (CML-BC)
• Juvenile myelomonocytic leukemia (JMML)
• Fanconi anemia (FA)
• Kostmann syndrome
• Shwachman syndrome
• Other bone marrow failure syndromes or low grade (< 5% bone marrow blasts) MDS
• Use of concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol
• Use of investigational agents within 30 days or any anticancer therapy for this malignancy within 2 weeks before study entry with the exception of intrathecal (IT) therapy, hydroxyurea, or low-dose cytarabine as stated above; the patient must have recovered from all acute toxicities from any previous therapy
• Systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment)
• Pregnant or lactating
• Any significant concurrent disease, illness, or psychiatric disorder that would compromise patient safety or compliance, interfere with consent, study participation, follow up, or interpretation of study results
• Prior chemotherapy, with the exception of hydroxyurea or low-dose cytarabine as stated above; the patient must have recovered from all acute toxicities from any previous therapy
• Patients with treatment related myeloid neoplasms with cumulative anthracyclines greater than 230 mg/m^2 doxorubicin equivalents

PRIMARY OBJECTIVES:

I. Evaluate the tolerability of five days of epigenetic priming with azacitidine and decitabine as a single agent deoxyribonucleic acid (DNA) methyltransferase inhibitor (DMTi) prior to standard acute myeloid leukemia (AML) chemotherapy blocks.

II. Evaluate the change in genome-wide methylation burden induced by five days of epigenetic priming and the association of post-priming genome-wide methylation burden with event-free survival among pediatric AML patients.

SECONDARY OBJECTIVES:

I. Describe minimal residual disease levels following induction I chemotherapy in patients that receive DMTi.

II. Estimate the event-free survival and overall survival of patients receiving a DMTi prior to chemotherapy courses.

EXPLORATORY OBJECTIVES:

I. Describe phenotypic changes in leukemia blasts as measured by flow cytometry following treatment with DMTi.

II. Identify all genomic lesions by comprehensive whole genome, exome and transcriptome sequencing on all patients.

III. Characterize changes in DNA methylation and gene expression following treatment with DMTi.

IV. Assess the prognostic value of minimal residual disease (MRD) by deep sequencing.

V. Study immune repertoire diversity over the course of treatment by deep sequencing of lymphocyte variable regions.

VI. Assess the stability of memory T cell subset-specific phenotypes and function in individuals who have undergone therapies that induce DNA methylation erasure and correlate changes in memory CD8 T cell phenotype and function with DNA methylation changes.

VII. Assess the effect of epigenetic priming on signaling using single cell phosphoproteomic analysis.

VIII. Identify active novel AML therapeutic agents.

IX. Examine the plasma metabolome of AML patients pre and post treatment with DMTi.

X. Examine cardiac function over the course of treatment.

OUTLINE:

To determine tolerability, priming with DMTi (azacitidine or decitabine) will be limited to Induction I and II during Part 1 of the study. If DMTi treatment is tolerated during Part 1, the investigators will go on to an Expansion Phase (Part 2) that includes DMTi priming prior to all chemotherapy blocks.

Treatment will consist of 5 blocks of conventional chemotherapy: Induction I, Induction II, Intensification I, Intensification II, and Intensification III.

RANDOMIZATION: Patients are randomized to receive 1 of 2 arms 5 days prior to Induction I:

ARM I: Azacitidine (AZA) intravenously (IV) over 10-40 minutes on days -4 to 0.

ARM II: Decitabine (DAC) IV over 1 hour on days -4 to 0.

INDUCTION I: Patients receive cytarabine IV over 30 minutes every 12 hours on days 1-10, dexrazoxane hydrochloride IV over 15 minutes on days 1, 3, and 5, daunorubicin hydrochloride IV over 6 hours on days 1, 3, and 5, and etoposide phosphate IV over 4 hours on days 1-5.

INDUCTION II: Patients receive their assigned DMTi days -4 to 0, fludarabine phosphate IV over 30 minutes on days 1-5, cytarabine IV over 4 hours on days 1-5, dexrazoxane hydrochloride IV over 15 minutes on days 3-5, idarubicin hydrochloride IV over 15 minutes on days 3-5, and filgrastim subcutaneously (SC) or IV over 15-30 minutes on days 1-7. Patients with FLT3-ITD after completion of other agents receive sorafenib tosylate orally (PO) once daily (QD) for 21 days.

Patients are then evaluated and assigned to either the low-risk arm, intermediate-risk arm, or the high-risk arm for Intensification therapy.

Patients with >= 5% blasts following Induction II will be considered refractory and will go off therapy. The rare high risk patient with an MRD < 0.1% following Induction I may proceed directly to stem cell transplant (SCT) after Induction II - if a suitable donor is available and the transplant can be performed without delay.

Priming with AZA or DAC prior to Intensification courses will only occur during the Part 2 expansion if it is found to be tolerated during Part 1. Patients will continue to receive the same DMTi they were randomly assigned to prior to Induction I. For patients with FLT3-ITD, treatment with azacytidine or decitabine will be limited to the first two cycles of Induction chemotherapy. They will not receive azacitidine or decitabine with Intensification therapy until their own tolerability phase is passed.

INTENSIFICATION I - LOW-RISK AML, INTERMEDIATE-RISK AML, and HIGH-RISK AML with no donor: Patients receive cytarabine IV over 2 hours every 12 hours and etoposide phosphate IV over 2 hours on days 1-5. Patients with FLT3-ITD after completion of other agents receive sorafenib tosylate PO QD for 21 days.

INTENSIFICATION I - HIGH-RISK AML with a donor:

Patients receive dexrazoxane hydrochloride IV over 15 minutes on days 3-5, mitoxantrone IV over 1 hour on days 3-5, and cytarabine IV over 2 hours every 12 hours on days 1-4 followed by stem cell transplant. Treatment related AML patients who have a donor but are not able to receive a SCT without delay will proceed to HR Intensification III and receive erwinia asparaginase and cytarabine. Patients with FLT3-ITD after completion of other agents receive sorafenib tosylate PO QD for 21 days.

Treatment related AML patients that are not able to receive a SCT should go off treatment following Intensification II.

INTENSIFICATION II: LOW-RISK AML, INTERMEDIATE-RISK AML, and HIGH-RISK AML with no donor: Patients receive dexrazoxane hydrochloride IV over 15 minutes on days 3- 5, mitoxantrone IV over 1 hour on days 3-5, and cytarabine IV over 2 hours every 12 hours on days 1-4. Patients with FLT3-ITD after completion of other agents receive sorafenib tosylate PO QD for 21 days.

INTENSIFICATION III CHEMOTHERAPY - INTERMEDIATE-RISK AML and HIGH-RISK AML with no donor: Patients receive cytarabine IV over 3 hours days 1, 2, 8, and 9 and erwinia asparaginase IV or intramuscularly (IM) over 1 hour days 2 and 9. Patients with FLT3-ITD after completion of other agents receive sorafenib tosylate PO QD for 21 days.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
St. Jude Children's Research Hospital

Principal Investigator
Tanja Andrea Gruber

• Primary ID AML16
• Secondary IDs NCI-2017-00928
• Clinicaltrials.gov ID NCT03164057